Diseases that cause muscle weakness include sarcopenia which progresses with aging, muscle atrophy caused by imbalance in protein metabolism or decrease in muscle uses, starvation, wasting diseases (cancer etc.), and acardiotrophy which progresses with aging.
Sarcopenia refers to a decrease in muscle strength due to a decrease in skeletal muscle mass during aging. Not only the decrease in skeletal muscle mass, which is the most important feature of sarcopenia, but also changes in the type of muscle fibers is observed. Type 1 and Type 2 decrease with aging at a similar rate, whereas Type 2 muscle fiber thickness does not change much but Type 1 muscle fiber thickness decreases significantly with sarcopenia. It has been reported that such sarcopenia causes aging and functional impairment among elderly people (Roubenoff R., Can. J. Appl. Physiol. 26, 78-89, 2001).
Although sarcopenia is caused by various factors, the research on each factor is still insufficient. It is caused by a reduction in growth hormone or a neurological change, a change in physical activity, a change in metabolism, an increase in a sex hormone level, fat or catabolic cytokines, and a change in the balance of protein synthesis and differentiation (Roubenoff R. and Hughes V A, J. Gerontol. A. Biol. Sci. Med. Sci. 55, M716-M724, 2000). A decrease in satellite cell activation is considered to be an important factor which causes a decrease in skeletal muscle mass which is the principal characteristic of sarcopenia. Satellite cells are small mononuclear cells located between the basement membrane and the sarcolemma of a muscle fiber. They are activated by stimulation, such as injury or exercise, to proliferate into myoblasts, and they fuse with other cells to form polynuclear muscle fibers as differentiation progresses. Thus, as the activity of satellite cells decreases, the capability of regenerating damaged muscle or the response to differentiation signals is reduced, resulting in decreased muscle formation.
Muscle atrophy is caused by nutritional deficiency or long-term muscle disuse, which is due to protein degradation by the breakdown of the normal balance of protein synthesis and degradation.
On the other hand, acardiotrophy is caused by starvation, wasting diseases (cancer, etc.), and senility, in which myocardial fibers become dry and thin and their nuclei get concentrated and vary in size. Thus, the volume of muscle fascicle and the whole heart get smaller, subepicardial adipose tissue is markedly decreased, and the coronary artery becomes bent. Brown wasting pigments (lipofuscin) appear around both ends of the nuclei of the myocardial fibers, and the whole heart gets brownish with the decrease of adipose tissue.
There are three main treatment methods for sarcopenia. The first is exercise. Exercise has been reported to increase skeletal muscle's protein synthesis in short term and increase muscle strength and motility of the elderly. However, it is unsuitable for a long-term treatment (Timothy J. Doherty, J. Appl. Physiol. 95, 1717-1727, 2003). The second is medication, and testosterone or anabolic steroid may be used, but it shows side effects such as inducing virilism in women and prostate symptoms in men, etc. Other approved therapeutic methods include DHEA (dehydroepiandrosterone) and growth hormone, which have been reported to be useful therapeutic methods at the sites that include SARMs (Selective Androgen Receptor Modulators) (D. D. Thompson, J. Musculoskelet Neuronal Interact 7, 344-345, 2007). Diet therapy is also known as a treatment method, but nutritional assessment shows that malnutrition or modern eating habits are unsuitable for maintaining a reasonable total body mass.
Recently, a stem cell therapy in which satellite cells are introduced into the body after the cells are isolated and differentiated in vitro, and a method for maintaining or strengthening muscles by directly activating satellite cells in the body to promote myogenesis have been introduced as the treatment methods for muscle weakness such as sarcopenia. (Shihuan Kuang and Michael A. Rudnicki, Trends in Molecular Medicine 14, 82-91, 2008).
Accordingly, in order to treat a muscle weakness-related disease, a method for differentiating muscle cells with a more fundamental method not inducing side effects is required, and thus it is necessary to develop a substance capable of promoting differentiation of myoblasts.